The unique gene complex, UGT1, encodes 2 bilirubin, 3 bilirubin-like, and 2 phenol UDP-glucuronosyltransferases in humans. The 5' region of the locus contains a tandem array of 7 unique exon 1s with its own 5' proximal TATA box, and the 3' region contains 4 common exons (2-5). Using sequence data of the normal UGT1 locus, we described 4 lethal mutations in six Crigler-Najjar, Type I patients. Three had the same 13- bp deletion in exon 2, predicted to truncate all isozymes encoded in the UGT1 locus at amino acid residue 365 (of 533); one contains a point mutation at codon 309 (gly to glu) in an 18-residue conserved sequence; one contains a point mutation at codon 375 (ser to phe); and one has a codon deleted at position 170 in the unique exon 1 of UGT1A converting a conserved diphenylalanine to a single phe which affects only HUG-Brl, the predominant bilirubin isozyme. By analyzing the 5' flanking region of each gene in combination with a reporter gene and by induction studies in monkey, we also demonstrated that the phenol transferase gene (UGT1), contrary to rodent models, lacks regulation by the Ah locus associated with chemical carcinogenesis. The therapeutic agent for hyperbilirubinemia, phenobarbital, enhances transcription of the UGT1C and UGT1D gene about 23 to 10-fold, respectively. The potential sites responsive to phenobarbital have been sequenced.